Novel diarylheptanoid analogs as antibacterial agents
L Shen et al
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J ¼ 8.3 and 1.2 Hz), 6.63 (1H, d, J ¼ 1.4 Hz), 6.54 (1H, d, J ¼ 1.0 Hz), 6.44 (1H,
(47%). 1H NMR (CDCl3, 400 MHz): d ¼ 6.91 (1H, d, J ¼ 8.4 Hz), 6.88 ꢀ6.85
d, J ¼ 8.1 Hz), 3.89 (3H, s), 3.88 (3H, s), 2.99ꢀ2.90 (1H, m), 2.85ꢀ2.70 (2H, m), 6.76 (1H, dd, J ¼ 8.2 and 1.8 Hz), 6.51 (1H, d, J ¼ 1.8 Hz), 6.37
(3H, m), 2.66ꢀ2.61 (1H, m), 2.58ꢀ2.52 (1H, m), 2.41ꢀ2.32 (2H, m), 2.02 (1H, d, J ¼ 1.8 Hz), 5.48 (1H, t, J ¼ 6.0 Hz), 5.07 (1H, t, J ¼ 6.2 Hz), 4.63
(1H, t, J ¼ 9.6 Hz), 1.75 ꢀ1.68 (1H, m), 1.58ꢀ1.37 (4H, m), 1.24ꢀ1.09 (2H,
(2H, d, J ¼ 6.3 Hz), 3.89 (3H, s), 2.86 ꢀ2.83 (2H, m), 2.61ꢀ2.58 (2H, m),
m) and 0.91ꢀ0.81 (1H, m)p.p.m. 13C NMR (CDCl3, 100MHz): d ¼ 149.4, 2.51 ꢀ2.48 (2H, m), 2.20 (2H, t, J ¼ 7.5 Hz), 2.12ꢀ2.01 (4H, m), 1.69 ꢀ1.59
148.7, 147.7, 147.1, 140.0, 133.7, 133.2, 128.8, 128.5, 126.3, 124.5, 124.0, 118.9, (9H, m), 1.57 ꢀ1.52 (2H, m) and 1.34 ꢀ1.26 (2H, m)p.p.m. 13C NMR
117.4, 112.4 (2C), 56.1 (2C), 53.9, 48.1, 36.3, 33.9, 33.5, 33.1, 29.9, 27.9 and (CDCl3, 100 MHz): d ¼ 211.0, 148.9, 148.6, 147.4, 147.2, 140.1, 134.0, 133.6,
23.5p.p.m. ESI-MS: calc. for C29H35NO3 [Mþ H]þ : 446.3; found: 446.4. 131.7, 124.5, 123.9, 122.9, 120.3, 119.0, 118.9, 115.8, 113.0, 66.6, 56.3, 43.7,
HPLC purity: 96.5% (254 nm), tR: 6.06 min; 98.5% (220nm), tR: 6.06min.
Compound 7c: 7c was prepared as described above for compound 7a from
41.6, 39.5, 33.1, 29.2, 27.8, 26.3, 25.7, 21.3, 17.7 and 16.6p.p.m. ESI-MS: calc.
for C30H39O4 [Mþ H]þ : 463.3; found: 463.4. HPLC purity: 98.7% (254nm),
4a (15.0 mg, 0.044 mmol) with benzylamine to give 9 mg of product (47%). 1H tR: 8.13 min; 99.4% (220nm), tR: 8.13min.
NMR (CDCl3, 400 MHz): d ¼ 7.32ꢀ7.24 (5H, m), 6.87 (1H, d, J ¼ 8.2 Hz),
Compound 13c: 13c was prepared as described above for compound 13a
6.83 (1H, d, J ¼ 8.2Hz), 6.75 (1H, dd, J ¼ 8.2 and 1.4 Hz), 6.68 (1H, dd, J ¼ 8.2 from 12 (21 mg, 0.064 mmol) with 1-bromohexane to give 20.5mg of product
and 1.5 Hz), 6.64 (1H, d, J ¼ 1.5 Hz), 6.49 (1H, d, J ¼ 1.3 Hz), 3.90 (3H, s),
(94%). 1H NMR (CDCl3, 400 MHz): d ¼ 6.92ꢀ6.86 (3H, m), 6.75 (1H, d,
3.89 (3H, s), 3.81 (1H, d, J ¼ 13.0Hz), 3.54 (1H, d, J ¼ 13.0 Hz), 2.73 (1H, t, J ¼ 8.2 Hz), 6.51 (1H, s), 6.33 (1H, s), 4.02 (2H, t, J ¼ 6.8 Hz), 3.90 (3H, s),
J ¼ 4.2 Hz), 2.69 (1H, t, J ¼ 4.2 Hz), 2.66ꢀ2.58 (1H, m), 2.42ꢀ2.34 (1H, m),
2.86 ꢀ2.83 (2H, m), 2.60 ꢀ2.58 (2H, m), 2.51 ꢀ2.48 (2H, m), 2.19 (2H, t,
2.13 (1H, t, J ¼ 9.8 Hz), 1.81 ꢀ1.72 (1H, m), 1.54ꢀ1.37 (4H, m), 1.25ꢀ1.09 J ¼ 7.5 Hz), 1.80ꢀ1.73 (2H, m), 1.58 ꢀ1.51 (2H, m), 1.43ꢀ1.36 (2H, m),
(2H, m) and 0.94 ꢀ0.83 (1H, m)p.p.m. 13C NMR (CDCl3, 100 MHz):
1.33 ꢀ1.27 (6H, m) and 0.85 (3H, t, J ¼ 6.6 Hz)p.p.m. 13C NMR (CDCl3,
d ¼ 149.3, 148.7, 147.5, 147.2, 133.8, 133.6, 128.4, 126.9, 124.6, 124.0, 118.8, 100 MHz): d ¼ 211.1, 149.3, 148.4, 147.6, 146.9, 133.9, 133.6, 124.7, 122.8,
117.7, 112.5 (2C), 56.2 (2C), 53.0, 51.1, 34.0 (2C), 33.2, 30.1, 28.0 and 119.2, 118.7, 115.3, 113.0, 69.7, 56.3, 43.7, 41.6, 33.0, 31.6, 29.3, 29.2, 27.8,
23.7p.p.m. ESI-MS: calc. for C28H34NO3 [Mþ H]þ : 432.3; found: 432.3. 25.6, 22.6, 21.3 and 14.0 p.p.m. ESI-MS: calc. for C26H35O4 [Mþ H]þ : 411.3;
HPLC purity: 96.0% (254 nm), tR: 5.92 min; 96.4% (220nm), tR: 5.92min.
Compound 7d: 7d was prepared as described above for compound 7a from
4a (15.1 mg, 0.044 mmol) with hexylamine to give 14mg of product (74%). 1H
found: 411.3. HPLC purity: 96.5% (254nm), tR: 7.93min; 99.0% (220nm),
tR: 7.93 min.
Compound 13d: 13d was prepared as described above for compound 13a
NMR (CDCl3, 400 MHz): d ¼ 6.98 (1H, dd, J ¼ 8.2 and 1.2 Hz), 6.87 (1H, d, from 12 (20 mg, 0.06mmol) with 1-bromooctane to give 25 mg of product
J ¼ 8.2 Hz), 6.86 (1H, d, J ¼ 8.2 Hz), 6.75 (1H, dd, J ¼ 8.2 and 1.2 Hz), 6.61 (93%). 1H NMR (CDCl3, 400 MHz): d ¼ 6.93ꢀ6.86 (3H, m), 6.75 (1H, d,
(1H, s), 6.50 (1H, s), 3.89 (3H, s), 3.87 (3H, s), 2.94ꢀ2.59 (5H, m), 2.46ꢀ2.36 J ¼ 8.2 Hz), 6.51 (1H, s), 6.34 (1H, s), 4.02 (2H, t, J ¼ 6.8 Hz), 3.90 (3H, s),
(2H, m), 1.82ꢀ1.74 (2H, m), 1.67ꢀ1.43 (6H, m), 1.33 ꢀ1.25 (6H, m),
1.21ꢀ1.13 (1H, m) and 0.94ꢀ0.85 (4H, m)p.p.m. 13C NMR (CDCl3,
2.86 ꢀ2.83 (2H, m), 2.61 ꢀ2.58 (2H, m), 2.51 ꢀ2.48 (2H, m), 2.20 (2H, t,
J ¼ 7.5 Hz), 1.81ꢀ1.73 (2H, m), 1.58 ꢀ1.51 (2H, m), 1.43ꢀ1.36 (2H, m),
100 MHz): d ¼ 149.7, 148.9, 147.6, 147.5, 133.4, 132.4, 125.1, 124.0, 118.8, 1.33 ꢀ1.23 (10H, m) and 0.86 (3H, t, J ¼ 6.6 Hz) p.p.m. 13C NMR (CDCl3,
118.0, 112.7, 112.6, 56.2, 56.1, 54.8, 45.9, 33.1, 32.3, 32.1, 31.4, 29.8, 28.0, 27.4, 100 MHz): d ¼ 211.1, 149.3, 148.4, 147.6, 146.9, 133.9, 133.5, 124.7, 122.8,
26.7, 23.5, 22.5 and 14.0 p.p.m. ESI-MS: calc. for C27H40NO3 [Mþ H]þ
:
119.2, 118.7, 115.3, 113.0, 69.7, 56.3, 43.7, 41.6, 33.0, 31.8, 29.4, 29.3, 29.2,
27.8, 25.9, 22.7, 21.3 and 14.1p.p.m. ESI-MS: calc. for C28H39O4 [Mþ H]þ
426.3; found: 426.4. HPLC purity: 99.5% (254 nm), tR: 6.15 min; 99.4%
(220nm), tR: 6.15min.
Compound 7e: 7e was prepared as described above for compound 7a from
:
439.3; found: 439.3. HPLC purity: 97.3% (254nm), tR: 8.25min; 98.5%
(220 nm), tR: 8.25 min.
4a (15.2 mg, 0.045 mmol) with cyclohexylamine to give 14.7mg of product Compound 13e: 2-Bromopropane (45ml, 0.48 mmol) and N,N-diisopropy-
(78%). 1H NMR (CDCl3, 400 MHz): d ¼ 6.98 (1H, d, J ¼ 8.1 Hz), 6.89 (1H, d, lethylamine (DIPEA, 25ml, 0.14mmol) were added to the solution of 12
J ¼ 8.4 Hz), 6.88 (1H, d, J ¼ 8.3Hz), 6.77 (1H, dd, J ¼ 8.1 and 1.2 Hz), 6.61 (15.7mg, 0.048 mmol) in acetonitrile (10 ml). The reaction mixture was heated
(1H, s), 6.52 (1H, d, J ¼ 1.2 Hz), 3.90 (3H, s), 3.89 (3H, s), 3.05ꢀ3.01 (1H,
under reflux overnight. After the reaction was complete (monitored by HPLC),
m), 2.76ꢀ2.66 (3H, m), 2.53ꢀ2.42 (2H, m), 2.10 ꢀ2.07 (1H, m), 1.88ꢀ1.84 the solvent was removed by evaporation. The residue was dissolved in EtOAc
(2H, m), 1.79ꢀ1.62 (6H, m), 1.53ꢀ1.43 (3H, m), 1.26 ꢀ1.17 (5H, m) and (10 ml) and washed with water. The organic layer was dried over anhydrous
0.94ꢀ0.84 (1H, m)p.p.m. 13C NMR (CDCl3, 100 MHz): d ¼ 149.7, 148.9,
Na2SO4 and then filtered. The filtrate was concentrated in vacuo to yield the
147.6, 147.5, 133.4, 132.3, 125.3, 124.0, 118.8, 118.3, 112.6 (2C), 56.2, 56.1, crude residue, which was further purified by flash column chromatography on
55.4, 52.5, 33.2, 32.8, 32.7, 32.3, 32.2, 29.8, 28.2, 25.1, 25.0 (2C) and 23.7p.p.m. silica gel (hexanes/ethyl acetate ¼ 91/9) to give 16mg of product (90%). 1H
ESI-MS: calc. for C27H38NO3 [Mþ H]þ : 424.3; found: 424.3. HPLC purity:
100% (254nm), tR: 5.98min; 99.8% (220nm), tR: 5.99min.
Compound 13a: The mixture of ketophenol 12 (18.6 mg, 0.057 mmol),
NMR (CDCl3, 400 MHz): d ¼ 6.93 (1H, d, J ¼ 8.2 Hz), 6.89 (1H, d, J ¼ 8.2 Hz),
6.86 (1H, d, J ¼ 8.3 Hz), 6.75 (1H, d, J ¼ 8.2 Hz), 6.50 (1H, s), 6.33 (1H, d,
J ¼ 2.1 Hz), 4.56ꢀ4.46 (1H, m), 3.90 (3H, s), 2.86ꢀ2.83 (2H, m), 2.60 ꢀ2.58
benzyl bromide (9.5ml, 0.08mmol), and potassium carbonate (15.7 mg, (2H, m), 2.51 ꢀ2.48 (2H, m), 2.19 (2H, t, J ¼ 7.5Hz), 1.58ꢀ1.51 (2H, m) and
0.114 mmol) in acetone (5ml) was refluxed for 6 h. The reaction mixture 1.33 ꢀ1.24 (8H, m)p.p.m. 13C NMR (CDCl3, 100MHz): d ¼ 211.1, 148.5,
was filtered and the filtrate was evaporated under reduced pressure. Dichloro- 148.2, 148.1, 147.6, 134.7, 133.7, 124.7, 122.8, 119.3, 118.8 (2C), 113.2, 72.7,
methane (20 ml) was added to the residue, and the solution was washed with 56.4, 43.7, 41.6, 33.0, 29.3, 27.8, 22.3 and 21.3p.p.m. ESI-MS: calc. for
water (2ꢂ 30 ml), the organic layer was filtered using a Biotage ISOLUTE C23H29O4 [Mþ H]þ : 369.2; found: 369.2. HPLC purity: 97.8% (254nm), tR:
phase separator (Biotage), evaporated and then purified by flash column 7.34 min; 99.0% (220nm), tR: 7.34min.
chromatography on silica gel (hexanes/ethyl acetate¼ 90/10) to give the
Compound 13f: At 0 1C, NaH (60% in mineral oil, 4.4 mg, 0.11mmol) was
added to a solution of 12 (18 mg, 0.055mmol) in DMF (2ml). To the resultant
product as a white powder (17.5mg; yield: 74%). 1H NMR (CDCl3,
400 MHz): d ¼ 7.31ꢀ7.30 (2H, m), 7.28 ꢀ7.27 (3H, m), 6.92 (1H, d, J ¼ 8.0 suspension, 3,3-dimethylallyl bromide (9.5ml, 0.083 mmol) was added at 0 1C.
Hz), 6.91 (1H, d, J ¼ 8.4 Hz), 6.83 (1H, dd, J ¼ 8.2 and 2.2 Hz), 6.78 (1H, dd, The mixture was then warmed up to room temperature and stirred for 2 h. The
J ¼ 8.2 and 2.0 Hz), 6.53 (1H, d, J ¼ 2.0 Hz), 6.34 (1H, d, J ¼ 2.0 Hz), 5.18 (2H,
s), 3.91 (3H, s), 2.85 ꢀ2.82 (2H, m), 2.60ꢀ2.57 (2H, m), 2.52ꢀ2.49 (2H, m),
2.19 (2H, t, J ¼ 7.4 Hz), 1.56ꢀ1.53 (2H, m) and 1.32ꢀ1.29 (2H, m)p.p.m.
reaction mixture was poured into water, and extracted with ethyl acetate.
The organic layer was dried over anhydrous Na2SO4, filtered and evaporated.
The crude product was purified by flash column chromatography on silica gel
13C NMR (CDCl3, 100MHz): d ¼ 211.0, 148.7, 148.5, 147.4, 147.3, 137.4, (hexanes/ethyl acetate¼ 91/9) to give 12.6mg of product (58%). 1H NMR
134.6, 133.6, 128.4, 127.7, 127.4, 124.6, 123.0, 119.1, 118.9, 116.5, 113.1, 56.3, (CDCl3, 400 MHz): d ¼ 6.92 (1H, d, J ¼ 8.3 Hz), 6.90 ꢀ6.85 (2H, m), 6.76 (1H,
43.7, 41.6, 33.0, 29.2, 27.8 and 21.3p.p.m. ESI-MS: calc. for C27H29O4 [Mþ
H]þ : 417.2; found: 417.2. HPLC purity: 99.6% (254 nm), tR: 7.52 min; 99.5%
(220nm), tR: 7.52min.
d, J ¼ 8.2 Hz), 6.50 (1H, s), 6.37 (1H, s), 5.48 (1H, t, J ¼ 6.5Hz), 4.60 (2H, d,
J ¼ 6.6 Hz), 3.89 (3H, s), 2.86ꢀ2.83 (2H, m), 2.61ꢀ2.58 (2H, m), 2.51 ꢀ2.48
(2H, m), 2.20 (2H, t, J ¼ 7.5 Hz), 1.73 (3H, s), 1.69 (3H, s), 1.58ꢀ1.52
Compound 13b: 13b was prepared as described above for compound 13a (2H, m) and 1.34ꢀ1.25 (2H, m) p.p.m. 13C NMR (CDCl3, 100 MHz):
from 12 (21 mg, 0.064 mmol) with geranyl bromide to give 13mg of product d ¼ 211.1, 148.9, 148.5, 147.3, 147.2, 137.1, 134.0, 133.5, 124.5, 122.9, 120.4,
The Journal of Antibiotics